Giant ankyrin-G regulates cardiac function

Abstract

Cardiovascular disease (CVD) remains the most common cause of adult morbidity and mortality in developed nations. As a result, predisposition for CVD is increasingly important to understand. Ankyrins are intracellular proteins required for the maintenance of membrane domains. Canonical ankyrin-G (AnkG) has been shown to be vital for normal cardiac function, specifically cardiac excitability, via targeting and regulation of the cardiac voltage-gated sodium channel. Noncanonical (giant) AnkG isoforms play a key role in neuronal membrane biogenesis and excitability, with evidence for human neurologic disease when aberrant. However, the role of giant AnkG in cardiovascular tissue has yet to be explored. Here, we identify giant AnkG in the myocardium and identify that it is enriched in 1-week-old mice. Using a new mouse model lacking giant AnkG expression in myocytes, we identify that young mice displayed a dilated cardiomyopathy phenotype with aberrant electrical conduction and enhanced arrhythmogenicity. Structural and electrical dysfunction occurred at 1 week of age, when giant AnkG was highly expressed and did not appreciably change in adulthood until advanced age. At a cellular level, loss of giant AnkG results in delayed and early afterdepolarizations. However, surprisingly, giant AnkG cKO myocytes display normal I Na , but abnormal myocyte contractility, suggesting unique roles of the large isoform in the heart. Finally, transcript analysis provided evidence for unique pathways that may contribute to the structural and electrical findings shown in giant AnkG cKO animals. In summary, we identify a critical role for giant AnkG that adds to the diversity of ankyrin function in the heart.

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Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant

“…Parasternal long-axis images inclusive of two-dimensional loops and freeze-frame, end-diastolic images were collected to measure end-diastolic LV cavity dimension (LVID, d) and posterior wall thickness (LVPW, d). Parasternal short axis images at the level of papillary muscles using M-mode were also collected to determine LVPW and LVID, in both systole (s) and diastole (d), as previously described ( 34 ). Parasternal short axis and M mode measurements were used to calculate functional parameters including fractional shortening (FS%) and ejection fraction (EF%).…”

“…Real-time PCR was performed as previously described ( 34 ). Briefly, total RNA from the mouse heart tissues was extracted with TRIzol Reagent (Invitrogen) following manufacturer's instructions; 1 μg of total RNA, treated with ezDNase, was used for the first-strand complementary DNA synthesis using SuperScript IV Vilo Master Mix (Thermo Fisher Scientific).…”

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